Phase 1 REGOMA-2 Trial Establishes Safe Dosing for Regorafenib Combination in MGMT-Methylated Glioblastoma
Key Insights
The phase 1 REGOMA-2 study demonstrated that regorafenib combined with temozolomide and radiotherapy was tolerable in patients with MGMT (search)-methylated, IDH (search) wild-type glioblastoma (search).
Maximum tolerated doses were established at 160 mg for adjuvant therapy and 120 mg for concurrent therapy, with only two dose-limiting toxicities observed across 21 patients.
The combination showed a weak pharmacokinetic interaction between regorafenib and temozolomide, with regorafenib displaying an 80% geometric mean ratio when given with temozolomide.
The combination of regorafenib with temozolomide and radiotherapy demonstrated acceptable tolerability in patients with MGMT (search)-methylated, IDH (search) wild-type glioblastoma (search), according to phase 1 data from the REGOMA-2 study presented at the 2025 Society of Neuro-Oncology Annual Meeting. The dose-finding trial successfully established maximum tolerated doses for both adjuvant and concurrent treatment approaches in this challenging brain cancer population.
Study Design and Patient Population
REGOMA-2 was a first-in-human, dose-finding study that enrolled 21 adult patients with MGMT (search)-methylated, IDH (search) wild-type glioblastoma (search) at two centers in Italy. The trial utilized a 3+3 design to explore regorafenib at escalating doses of 80 mg, 120 mg, and 160 mg across two distinct treatment cohorts.
Cohort A (n=9) evaluated regorafenib plus maintenance temozolomide following standard chemoradiotherapy, while cohort B (n=12) examined regorafenib administered concurrently with chemoradiotherapy and temozolomide. Patients in cohort A were required to have completed standard temozolomide and chemotherapy courses with MRI-documented stable disease, while cohort B patients needed prior tumor resection within seven weeks of first regorafenib dose.
The median ages in cohorts A and B were 52 years and 53 years, respectively. All patients had grade IV disease, adequate laboratory values, and had recovered from surgical effects.
Safety Profile and Dose-Limiting Toxicities
The safety profile proved favorable across both treatment approaches. In cohort A, no patients experienced dose-limiting toxicities at any regorafenib dose level, allowing escalation to the standard 160 mg dose as the maximum tolerated dose.
"The safety of regorafenib combination with temozolomide and radiation therapy was very good, with no unexpected toxicity due to regorafenib," said Giuseppe Lombardi, MD, PhD, head of the Neuro-Oncology Unit at Veneto Institute of Oncology IOV-IRCCS (search) and the study's lead investigator.
Cohort B experienced two dose-limiting toxicities at the 160 mg dose level: one case of grade 3 hypertransaminasemia (search) and one instance of grade 4 thrombocytopenia (search) occurring on the last day of radiotherapy. This established the maximum tolerated dose for concurrent therapy at 120 mg.
Additional safety events included grade 2 thrombocytopenia (search) requiring treatment delays in cohort A, and grade 3 hypertension (search) and hyperbilirubinemia (search) in cohort B. No grade 3-4 adverse events occurred at the lowest dose level.
Pharmacokinetic Interactions
The study revealed a weak but significant pharmacokinetic interaction between regorafenib and temozolomide. When administered in combination, regorafenib demonstrated a significant reduction in area under the concentration curve (P = 0.038), with a geometric mean ratio of 80% (90% CI, 64%-98%) compared to monotherapy administration.
Clinical Implications and Next Steps
The researchers concluded that the 120 mg dose represents the recommended phase 2 dose for regorafenib in combination with standard Stupp therapy. "The MTD of 120 mg can be considered the RP2D of regorafenib for combination with standard Stupp therapy in a phase 2 trial," Lombardi and colleagues wrote.
The study's primary endpoints focused on dose-limiting toxicity incidence, adverse event rates, and treatment discontinuation due to toxicity. Secondary endpoints included pharmacokinetic measures, treatment response, progression-free survival, quality of life, and overall survival.
Lombardi indicated that preliminary efficacy analyses are ongoing, with plans for a phase 2 randomized study to further evaluate the combination's therapeutic potential. "We [also] reported very interesting [preliminary efficacy] results, and the next step will be to [evaluate the regimen in] a phase 2 randomized study," he noted.
The REGOMA-2 findings provide a foundation for advancing regorafenib combination therapy in MGMT (search)-methylated glioblastoma (search), a patient population that may benefit from enhanced treatment approaches beyond standard care.